Abstract

The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 μmol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 μmol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 μmol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 μmol/kg) and mecamylamine (12 μmol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1–13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylaminevia the kappa receptor-mediated opioid neuronal system.

Footnotes

↵1 This study was supported in part by grants from the Kowa Life Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Japan Smoking Research Foundation, the Science Research Promotion Fund from Japan Private School Promotion Foundation and INSERM/JSPS Joint Research Project, and by Grants-in-Aids for Scientific Research (No. 09672340) from the Ministry of Education, Science and Culture, Japan.